Insight into the Aseptic Spray Drying Process

December 17, 2014

7 Min Read
Insight into the Aseptic Spray Drying Process
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Having just gone through the design and Factory Acceptance Test (FAT) of some new spray drying systems, I noted the complexity of design required. While there are thousands of spray dryers in use, supplied by many different vendors, building a truly aseptic plant presents some major challenges requiring some innovative solutions.
    In the design phase of a spray dryer for aseptic pharmaceutical processes, particular attention has to be given to quality standards such as ASME Bioprocessing Equipment (BPE) and current Good Manufacturing Practices (cGMP). Filtration, draining, cold spots, steam supply, materials science, CIP/ SIP equipment, and zoning are all areas that also need particular attention. Furthermore, the sequence of control has to be exact to create a sterile environment. The requirement for the selection of equipment that is ‘clean’ also seems to conflict with the need for usability and ergonomic design. In short, there is no ‘easy’ engineering solution for a truly aseptic system.

Sterilization and Sterilization Levels
The pharmaceutical industry currently uses steam as the standard to sterilize product contact parts. In large spray drying plants, steam-in-place requires components that withstand up to two bar pressure of steam as well as the ability to operate in a vacuum, used to ensure that air does not prevent steam from accessing all the internal voids within the machinery. Operation at 2 bar necessitates the construction of an ASME vessel but this needs to be combined with GMP and aseptic design requirements.
    It should be mentioned that ‘dry heat’ sterilization has been reviewed but that this sterilization method cannot prevent off gassing or the release of fibers at the elevated temperatures required in spray drying. Subsequent testing of filter integrity has also shown contamination issues that cannot be effectively resolved.
    In brief, the guideline for aseptic processing (Sterility Assurance Level or SAL) currently suggests a ‘kill number’ of three to six logs of an appropriate biological monitor/reduction. There is still much to be defined in the guidance of characteristics and resistance in the choice of the monitor, which is currently either Geobacillus stearothermophilus or Bacillus subtilis.
    A SAL of 10-6 means that for every one million items sterilized there may be just one that contains a bacteria that has survived the process. This statistical probability is used because it is impossible to prove that all bacteria have been killed during sterilization. In practice, the theoretical degree of processing to achieve the desired SAL is determined and then routine processing is set to a higher level in order to achieve overkill. In a pharmaceutical sterilization with six-log SAL where a 12-log reduction is required, the sterilization time should be: 2.5 x 12 = 30 minutes
    Most biological indicators have a population of 106 spores and a six-log reduction is required to reduce the population to one. Another six-log reduction is required for a SAL value of 10-6.

Spray Drying Equipment
After validating an ASME vessel, producing support systems for heating, filtration, vacuum, CIP/SIP skids, and insulation, and implementing a sophisticated control strategy, what are the challenges designers have with the components within the spray dryer?
    A spray dryer has a large mass of stainless steel and requires a great deal of energy to bring the system up to temperature. To speed up this process and increase the versatility and efficiency of the system, a fast heat system that heats is incorporated into the dryer’s steel inner wall and greatly reduces start up time.
    The air disperser/guide unit is at the heart of the spray dryer. A sophisticated design for this part of the system was developed using computation fluid dynamics (CFD). It precisely conducts the sterile processed gas into the chamber to overlay the specific spray nozzle technology being utilized. This produces the desired flow of the spray into the drying chamber and optimizes the evaporation process. This spray dryer system uses a precision low mass guide in the disperser. The low mass of this guide reduces heat soak and conduction into the nozzle.
    The nozzle, or liquid atomizing, technology with the spray dryer produces a large surface area or cloud from which effective evaporation can take place. There are three basic atomization types that are routinely used: rotary, pressure/hydraulic, or two fluid nozzles/atomizers.
    The usual concentration of solids in a liquid suspension ranges from 4% to 40% or more, depending on viscosity. A two fluid nozzle will typically produce particles between less than one and 20 microns and a viscosity of less than 250 cps works well in the system. When larger particles are required single fluid technology is a better choice but this uses an orifice in the 0.03-in. range (depending on fluid capacity) and so requires a clean fluid as clogging can be an issue. This system also needs to operate at very high pressures. A rotary atomizer can produce larger particles with a narrower size distribution and is less prone to blocking but it has many moving parts, bearings, seal, etc., and, as such, is not suitable for aseptic use. Emerging approaches include the use of ultrasonic technology but, at present, the atomization collapses when introduced into the air stream of the disperser. The two fluid atomizer is, therefore, generally best suited for aseptic processing.
    The choice of spray dryer heating systems for aseptic applications are limited due to GMP, sterility, temperature, and cleaning requirements, meaning a filter cannot be fitted after the heater. Heat exchangers are therefore used. Specifically designed units using hot oil as the heating medium and capable of heating to 260-315°C are the preferred choice. The oil is pumped through the outer tube chamber area, conducting heat to the outer layer of gas tubes. Heat is transferred to the processed gas as it travels through these tubes. It should be noted that there are heater systems which can deliver greater thermal efficiency, but this solution offers the most effective, sterilizable solution.
    Some spray dryers use a chemical clean in place (CIP) process during which the processor is depyrogenated. The processor is sterilized in place (SIP) with steam that is between one and two bar. As referred to earlier, this requires the vessel to be pressure rated to the ASME code. Sterilization occurs at a minimum of 121°C, with some applications using temperatures as high as 131°C. The requirement for CIP, SIP, and a pressure rating makes the aseptic drying system inherently more complex than a standard GMP dryer.
    The management of the CIP skids is a separate subject and will not be addressed in this article. There are, however, a number of issues that should be highlighted as CIP coverage is critical in the aseptic system. The spray devices are placed in specific locations to provide maximum coverage without spoiling or flooding. This can lead to areas where drainage or flow problems can occur, which become evident during riboflavin coverage tests. If system points do not drain quickly enough, the following wash liquid backs up and disrupts the drainage, which can leave riboflavin behind and lead to a ‘zoning’ issue during the cleaning process.
    Tank washers and spin technology cannot be used as it cannot be guaranteed that production of particulate generated will not be launched into the sterile system. Static spray balls are, therefore, utilized. To remove zoning and drainage issues, systems are designed to ensure gravity helps with drainage with low points and drains for transverse piping where sloping is not possible. Testing has shown that concentrating on the upper section of tanks and piping generates a cascade of CIP liquid which creates effective wall washing and good cleaning results.

Summary
To ensure aseptic processing, some of the traditional components used within standard spray drying technology cannot be utilized. Systems need to be carefully engineered to make cleaning and sterilization easier – which can result in a more complicated overall solution.

Martin Mogavero is technical support manager at SPX Flow Technology Systems Inc. (Elkridge, MD). For more information, visit www.spx.com.
 
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